Topology of His Residues in Amyloid β Protein Fibrils

Abstract

Oxidatively damaged lipid membranes are known to promote the aggregation of amyloid β (Aβ) proteins into fibrils. When lipid membranes contain ω-6 polyunsaturated fatty acyl chains and subjected to oxidative stress, 4-hydroxy-2-nonenal (HNE), a highly reactive short chain alkenal, is typically produced. We previously demonstrated that HNE modifies the three His residues of Aβ proteins by Michael addition, which increases their affinity for the lipid membrane surface, and promotes the aggregation of unmodified Aβ proteins into fibrils. In this report, HNE-promoted Aβ fibrils were studied by negative-staining electron microscopy and shown to have morphologies identical to fibrils formed without HNE. The binding of antibodies specific for HNE-His adducts was studied by colloidal gold immunoelectron microscopy. Results indicate that the His13 residue of Aβ protein (the 42 residue form) was inaccessible, while the His14 residue was accessible. These results agree with some of the published molecular structure models of Aβ protein fibrils.